The mission of the Stable Isotope & Metabolomics Core (SIMC) is to provide guided metabolite and substrate flux determinations in complex in vivo metabolic rodent models and for human clinical investigation for members of the Einstein-Mount Sinai Diabetes Research Center (ES-DRC). The SIMC provides an array of in vitro metabolic methodologies that augment in vivo investigations. These services provide investigators with specialized assays to determine substrate flux dynamics and metabolite profiles at the organelle, cellular, tissue and whole body level thereby elucidating the integrative network of disorders in glucose, protein and lipid metabolism. Through these collaborative efforts with the other Cores of the ES-DRC, the effects of defined pharmacological, dietary, environmental and genetic alterations are thoroughly characterized for their effects on glucose and lipid homeostasis, insulin action, and metabolism. The role of candidate molecules in relevant tissues (i.e., neurons, hepatocytes, skeletal muscle, adipocytes and beta cells) that are related to glucose homeostasis can be specifically delineated by thorough and definitive analyses using in vivo and in vitro experimentation with a step-wise guided approach in rodents and humans as well as in cell lines. To accomplish these goals, the SIMC will: 1) perform in vivo stable isotope substrate flux assays for the determination of rates of protein synthesis, lipogenesis, peripheral glucose disposal, hepatic glucose recycling, glucose-glycerol cycling and glucose-lactate cycling; 2) determine glycolysis (extracellular acidification rates) and mitochondrial oxygen consumption (mitochondrial respiration) in isolated cells, tissue explants or tissue culture, using Seahorse Biosciences Flux Analyzers, as well as more comprehensive stable isotope flux assessments; 3) perform targeted hypothesis-driven assessments of plasma and tissue metabolite profiles for key metabolites in the glycolytic/gluconeogenic, pentose phosphate, and tricarboxylic (TCA) cycle pathways, and lipid metabolism, including fatty acid, fatty acyl CoA and fatty acyl carnitine profiles; 4) provide mentorship and assistance with protocol development , which uses mass spectrometer-based flux and metabolite profiling methods for the evaluation of molecular biochemical targets relevant to the control of glucose and fatty acid homeostasis; and 5) coordinate these efforts with other ES-DRC and Institutional Core facilities at Einstein and Mount Sinai. All of these services are available to investigators new to diabetes research, as well as to investigators working on diabetes-related projects that can be enriched and extended by the use of the expertise and facilities of this Core.